Cydodextrins, sometimes referred to as Schardinger's dextrins, were first isolated by Villiers in 1891 as a digest of Bacillus amylobacter on potato starch. The foundations of cydodextrin chemistry were laid down by Schardinger in the period 1903-1911. Until 1970, however, only small amounts of cyclodextrins could be produced in the laboratory and the high production cost prevented the usage of cyclodextrins in industry. In recent years, dramatic improvements in cyclodextrin production and purification have been achieved and cyclodextrins have become much less expensive, thereby making the industrial application of cyclodextrins possible.
Cyclodextrins are cyclic oligosaccharides with hydroxyl groups on the outer surface and a void cavity in the center. Their outer surface is hydrophilic, and therefore they are usually soluble in water, but the cavity has a lipophilic character. The most common cyclodextrins are .alpha.-cyclodextrin, .beta.-cyclodextrin and .gamma.-cyclodextrin, consisting of 6, 7 and 8 .alpha.-1,4-linked glucopyranose units, respectively. Thus cyclodextrins have the general formula: ##STR1## wherein n is 4, 5, or 6. The number of these units determines the size of the cavity. In the case of .alpha.-cyclodextrins, n is 4. For .beta.- and .gamma.-cyclodextrins, n is 5 and 6, respectively.
Cyclodextrins are capable of forming inclusion complexes with a wide variety of hydrophobic molecules by taking up a whole molecule (a "guest molecule"), or some part of it, into the void cavity. Common cyclodextrin derivatives are formed by alkylation (e.g., methyl-and-ethyl-.beta.-cyclodextrin) or hydroxyalkylation of .alpha.-, .beta.-, and .gamma.-cyclodextrin or by substituting the primary hydroxyl groups with saccharides (e.g., glucosyl- and maltosyl-.beta.-cydodextrin). Hydroxypropyl-.beta.-cyclodextrin and its preparation by propylene oxide addition to .beta.-cyclodextrin, and hydroxyethyl-.beta.-cyclodextrin and its preparation by ethylene oxide addition to cyclodextrin, were described in a patent of Gramera et al. (U.S. Pat. No. 3,459,731, issued August 1969).
Although cyclodextrins have been used to increase the solubility, dissolution rate and/or stability of a great many compounds, it is also known that there are many drugs for which cyclodextrin complexation either is not possible or yields no advantages. See J. Szejtli, Cyclodextrins in Drug Formulations: Part II, Pharmaceutical Technology, 24-38, August, 1991.
U.S. Pat. No. 5,134,127 to Stella et al., herein incorporated by reference, discloses cyclodextrin derivatives wherein the glucopyranose units are substituted by (C.sub.2-6 alkylene)-SO.sub.3 groups, herein referred to as sulfoalkyl ether cyclodextrins. The degree of substitution, calculated as the average number of sulfoalkyl ether groups per cyclodextrin ring, range from 1.2 to about 7. These cyclodextrins are advantageous, inter alia, because they possess a very low level of toxicity and a high aqueous solubility. They are suitable for use as clathrating agents with drugs to provide complexes which are useful in parenteral and other pharmaceutical formulations.
Sulfoalkyl ether cyclodextrins as disclosed in U.S. Pat. No. 5,134,127 are made by treating an unsubstituted (.alpha.-, .beta.-, or .gamma.-) cyclodextrin starting material with an alkyl sultone in the presence of a base. Residual cyclodextrin is undesirable since it is a known nephrotoxin. Residual alkyl sultone, an alkylating agent, is also toxic and it is accordingly desirable that residual alkyl sufltone levels be as low as possible, preferably essentially absent, in the crude and/or finished sulfoalkyl ether cyclodextrin product. A method which provided for low levels of both, and which otherwise allowed achieving low levels of other by- products, would be a useful addition to the cyclodextrin art.